Rates of both obesity and diabetes continue to escalate and with them come rising monetary and human costs. Growing evidence links gut secreted factors as crucial for regulating both food intake and the levels of glucose in the blood. Glucagon-like-peptide-I (GLP-I) is a gut peptide with a broad role in the regulation of nutrient ingestion and disposition. GLP-I is produced in the intestine as well as in a restricted set of neurons in the hindbrain, and a single GLP-I receptor (GLP-I R) is expressed in pancreatic islets as well as neurons controlling autonomic and neuroendocrine function in the hypothalamus, amygdala and caudal brainstem. Previously it was thought that intestinal GLP-I and central GLP-I operated as independent systems, the former regulating glucose metabolism and the latter behavioral responses, particularly food intake. Recent evidence has challenged this view and it is increasingly apparent that there is overlapping activity between the peripheral and CNS GLP-I systems. In particular, it now appears that signaling through CNS GLP-I receptors regulates blood glucose, although it is not yet clear whether the signal is from GLP-I secreted in the brain, the gut or both. Moreover, peripherally administered GLP-I R agonists, like exendin-4 (Ex-4), cause weight loss in rodents and humans in addition to improving glucose tolerance, but it is unclear how this effect is mediated. The specific populations of CNS GLP-I receptors responsible for regulating blood glucose and the anorectic actions of Ex-4 remain unclear. Thus, the overarching goal of this proposal is to determine how the peripheral and central GLP-I systems interact to control food intake and glucose metabolism. Our first aim will be to determine the key sites of endogenous GLP-I and exogenous Ex-4 to regulate food intake and body weight using both pharmacological and tissue specific genetic knockdowns. Our second aim will be to determine the key sites of endogenous GLP-I and exogenous Ex-4 to regulate peripheral glucose levels. Again we will use a combination of site-specific delivery of pharmacological antagonists and tissue-specific genetic knockdowns of the GLP-I receptor. Determining the mechanisms of CNS GLP-I signaling is important for understanding carbohydrate and energy balance. Furthermore, the advent of pharmaceuticals that utilize GLP-I R signaling to treat diabetes makes understanding the physiology of GLP-I directly applicable to clinical care.